Prostate cancer has the highest age-adjusted incidence rates and is the second leading cause of death of any malignancy in men 65 years and older. The Baltimore Longitudinal Study of Aging (National Institute on Aging) suggests that prostate cancer begins early in middle age. Tissue based analysis of the aging prostate reveals that the prostate cancer precursor, prostatic intraepithelial neoplasia (PIN), starts in the 3rd and 4th decades, with the lesions becoming more extensive in older men. As a potential etiology, an accumulating body of basic research data suggests that normal and neoplastic prostate cells are subjected to a relentless barrage of genome-damaging stresses, and that dietary components and male sex steroids might modulate the level of genome threatening insults. Molecular alterations have been identified in histologically benign prostate cells, which may represent some of the earliest changes required in the development of prostate cancer. Therefore, the elucidation of these early molecular alterations in histologically benign cells will be of great significance in determining prostate cancer risk at a younger age and for monitoring patients on preventive trials. Our long-term goal is to identify the earliest detectable molecular events in the development of prostate cancer seen with aging. This proposal will test the central hypothesis that discrete populations of histologically benign appearing prostate epithelial cells over express genes that are harbingers of PIN and prostate cancer. Our group has identified, alpha-methylacyl-CoA racemase (AMACR) as one of the earliest up-regulated genes in the development of prostate neoplasia. AMACR protein expression is seen predominantly in prostate cancer and PIN. Most relevant to this proposal is the observation that rare, histologically benign glands adjacent to PIN express AMACR, suggesting prostate cells that have undergone some, but not all, molecular alterations required to develop a neoplastic phenotype. We plan to test our central hypothesis and accomplish the overall objectives of this application by pursuing the following specific aims: Aim 1: Determine the earliest overexpressed genes in the development of prostate neoplasia; Aim 2: Determine the frequency of harbinger genes in a cross sectional study on the aging prostate; Aim 3: Determine the optimal harbinger genes to assess risk from prostate needle biopsies.